Inflammation is generally required for the development of insulin resistance in obese animals, consistent with demonstrations that inflammation predisposes obese people to be metabolically unhealthy. In contrast, obese people with negligible inflammation are often metabolically healthy. The role of inflammation as an accelerator of obesity-associated metabolic decline indicates that an inflammatory signature can predict the transition from obese/metabolically healthy to obese/insulin resistant/type 2 diabetes (T2D). Our proposed work will comprehensively define inflammatory signature(s) during T2D etiology and pathogenesis to fill critical gaps in 1. Identifying people most likely to transition to T2D in response to obesity; 2. Pinpointing treatments to new targets thus improve the currently modest efficacy of anti-inflammatory drugs in T2D; and 3. Using targeted therapies to uncouple obesity from inflammatory-mediated complications such as T2D and cardiovascular disease. We have used a multivariate mathematical approach to identify a previously unappreciated inflammatory signature that differentiates obese/non-T2D, obese/pre-T2D and obese/T2D subjects. This signature includes multiple T cell cytokines, many of which are preferentially produced by the Th17 or Th1 T cell subsets. Our identification of a human T cell inflammatory signature coupled with the proposed extention of the analyses to additional putative sources of diabetogenic inflammation provide unique opportunities to address important outstanding questions in the relationship between inflammation and T2D pathogenesis. We will test the hypothesis that a T cell signature that distinguishes T2D from non-T2D subjects is a predictive biomarker for T2D pathogenesis through a longitudinal multiple-PI project involving experts in human immunometabolism, cytokine network modeling and clinical research in obesity. The possibility that a cytokine signature validated by the proposed work will identify people who require more intensive monitoring, intervention or new anti-inflammatory drugs to delay or prevent obesity-associated T2D has tremendous potential to change clinical practice, emphasizing both the impact and the urgency of the project.